Our major objectives are to examine cell replication and repair of DNA damage as a function of aging in human cells in vitro and in rat and mouse tissues in vivo. A technique has been developed to examine cell replication in vivo in intact animals utilizing the BrdU-differential staining techniuqe. Results obtained with this technique indicate a decline in cell replication as a function of aging. Further research will be directed not only at defining this decline in cell replication but also at investigating the mechanisms for this functional loss. The BrdU-differential staining techniques have also been applied to examining DNA repair by analyzing the frequencies of sister chromatid exchanges (SCE) induced by various DNA damaging agents in vivo in mouse and at bone marrow cells and in vitro in culture human fibroblasts. In all these systems, a significant decrease in MMC-induced SCE was observed in the older cell populations. The mechanism of the altered response to DNA damage as manifested by diminished SCE is being investigated.